P278	Vasorelaxant effect of parathyroid hormone-related peptide (PTHrP) in the rat heart: evidence for endothelium involvement independent from nitric oxide formation.
G.Ross, A.Dolf, M.Heinemann, K-D.Schlüter
Physilogisches Institut, Gießen, DE.

PTHrP is known as a strong vasodilator. The mechanisms by which its effect is evoked in coronary vessels have not been worked out. This study was performed to decide whether the endothelium is involved in the relaxant effects of PTHrP. Methods: Rat hearts were perfused in the Langendorff mode under either flow or pressure constant conditions. Changes in coronary resistance were investigated by analysing changes in perfusion pressures and flow rates. Results: If the coronary vessels were pre-constriceted by L-nitro-arginine (L-NA, 100 µmol/l), PTHrP (1-34, 100 nmol/l) reduced perfusion pressure within 5 min to basal levels (from 112±13 mmHg to 55±8 mmHg). This effect was preserved after washout of the peptide. Inhibition of either adenylyl cyclase/protein kinase A-dependent pathways by H89 (1 µmol/l) or indomethacin (1 µmol/l) sensitive pathways, didnt attenuate the early onset of dilatation. However, the effect was converted into a transient one (10 min after treatment: PTHrP: 47±2 mmHg, PTHrP+H89: 84±6 mmHg, PTHrP+Indomethacin: 57±1 mmHg). Depolarisation of the vessels by high potassium (KCl: 27 mmol/l), completely attenuates the dilating effect of PTHrP (basal: 96±18, PTHrP: 98±24), but didnt modify the responsiveness to either nitroprusside (1 µmol/l) or isoprenaline (10 nmol/l). Denudation of the endothelium by collagenase (20 mg/ml) treatment produced an increase in perfusion pressure (from 56±3 to 98±12 mmHg). Under these conditions, PTHrP didnt evoke any effect on perfusion pressure (basal:140±19 mmHg, PTHrP: 138±18 mmHg). Conclusion: The results suggest that PTHrP exerts its strong vasodilative effect on rat coronary vessels via generation of EDHF. Furthermore, this effect seems to be endothelium-dependent but not NO-dependent.

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